BACKGROUND GSK3640254 (GSK'254) is a next-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor with pharmacokinetics (PK) supporting once-daily therapy. METHODS This phase IIa double-blind (sponsor-unblinded), randomized, placebo-controlled, adaptive study evaluated antiviral effect, safety, tolerability, and PK of once-daily GSK'254 monotherapy administered with food (moderate-fat meal) in HIV-1-positive, treatment-naive adults. In part 1, participants received GSK'254 10 or 200 mg for 10 days. In part 2, participants received GSK'254 40, 80, or 140 mg for 7 days, modified from 10 days by a protocol amendment to decrease potential for resistance-associated mutations (RAMs). The primary endpoint was maximum change from baseline in HIV-1 RNA. RESULTS Maximum changes in HIV-1 RNA of -0.4, -1.2, -1.0, -1.5, and -2.0 log10 occurred with GSK'254 10, 40, 80, 140, and 200 mg, respectively. Regardless of dosing duration, doses ≥40 mg resulted in ≥1-log10 declines in HIV-1 RNA. Plasma PK was generally dose proportional to 140 mg but non-proportional between 140 and 200 mg. Four participants in the 200-mg group developed RAMs on day 11 in part 1, 1 with phenotypic resistance. No RAMs occurred in part 2. Adverse events (AEs) were reported by 22 (65%) participants; headache was the most common (n = 4). Two non-drug-related serious AEs occurred. All AEs were of mild-to-moderate intensity, except for 2 grade 3 non-drug-related AEs in 1 participant. CONCLUSIONS This monotherapy study established a dose-antiviral response relationship for GSK'254. No safety or tolerability concerns were noted. These results supported dose selection for the ongoing phase IIb study (ClinicalTrials.gov: NCT04493216). CLINICAL TRIALS REGISTRATION NCT03784079.

中文翻译：

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下一代成熟抑制剂 GSK3640254 的抗病毒功效、安全性、耐受性和药代动力学的 IIa 期概念验证评估。

背景 GSK3640254 (GSK'254) 是下一代 1 型人类免疫缺陷病毒 (HIV-1) 成熟抑制剂，其药代动力学 (PK) 支持每日一次的治疗。方法 该 IIa 期双盲（发起人非盲法）、随机、安慰剂对照、适应性研究评估了每日一次 GSK'254 单一疗法与食物（中等脂肪餐）一起治疗 HIV 的抗病毒效果、安全性、耐受性和药代动力学-1阳性，未接受过治疗的成年人。在第 1 部分中，参与者连续 10 天服用 GSK'254 10 或 200 毫克。在第 2 部分中，参与者接受 GSK'254 40、80 或 140 mg，为期 7 天，根据协议修正案从 10 天修改为减少耐药相关突变 (RAM) 的可能性。主要终点是 HIV-1 RNA 相对于基线的最大变化。结果 HIV-1 RNA 的最大变化为 -0.4、-1.2、-1.0、-1.5、和 -2.0 log10 分别发生在 GSK'254 10、40、80、140 和 200 mg 的情况下。无论给药持续时间如何，≥40 mg 的剂量都会导致 HIV-1 RNA 下降≥1-log10。血浆 PK 通常与 140 mg 的剂量成比例，但在 140 和 200 mg 之间不成比例。200 毫克组中的四名参与者在第 1 部分的第 11 天出现了 RAM，其中 1 人具有表型抗性。第 2 部分未发生 RAM。22 名 (65%) 参与者报告了不良事件 (AE)；头痛是最常见的 (n = 4)。发生了两个非药物相关的严重 AE。除了 1 名参与者的 2 次 3 级非药物相关 AE 外，所有 AE 均为轻度至中度强度。结论 该单一疗法研究建立了 GSK'254 的剂量-抗病毒反应关系。没有注意到安全或耐受性问题。这些结果支持正在进行的 IIb 期研究（ClinicalTrials.gov：NCT04493216）的剂量选择。临床试验注册号 NCT03784079。